Deoxynivalenol induces liver injury by inhibiting the p62-Keap1-Nrf2 signaling pathway via overactivation of PINK1/Parkin-mediated mitophagy.

Deoxynivalenol (DON), a prevalent mycotoxin contaminant in food and feed, poses severe threats to both human and animal health. However, the mechanisms underlying DON-induced hepatotoxicity remain unclear. In this research, mice and the immortalized normal mouse hepatocyte cell line (AML-12) were treated with DON at 0 -4.8 mg/kg (7 d) and 0 -6.4 μM (24 h), respectively. Our results indicated that DON induces overactivation of PINK1/Parkin-mediated mitophagy, leading to mitochondrial damage. This activation promotes apoptosis, oxidative stress, inflammation, and lipid metabolism disorder, as confirmed through the use of mitophagy inhibitors (Mdivi-1) and si-PINK1. Moreover, DON simultaneously suppresses the p62-Keap1-Nrf2 cytoprotective pathway, thereby compromising the cellular defense system and amplifying injury. Notably, p62 overexpression mitigates DON-induced liver injury through competitive binding to Keap1, promoting Nrf2 nuclear translocation. Overall, our findings reveal that DON induces liver injury by inhibiting the p62-Keap1-Nrf2 signaling pathway via overactivation of PINK1/Parkin-mediated mitophagy.